KS-25, a newly developed synthetic TGF-β inhibitor, mitigates insulin resistance and liver steatosis in mice fed a high-fat diet

초록

Background and aims: Obesity-induced inflammation in visceral adipose tissue (VAT) triggers the release of pro-inflammatory cytokines, contributing to systemic inflammation and insulin resistance, which in turn accelerate the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). The Transforming Growth Factor (TGF)-β/Smad3 signaling pathway plays a critical role in mediating these inflammatory processes within VAT. In this study, we explore the potential therapeutic effects of KS-25, a novel synthetic verbenone derivative, in inhibiting TGF-β/Smad3 signaling to mitigate VAT inflammation, insulin resistance, and MASLD in high-fat diet-induced obese mice. Materials and methods: MASLD was induced in male C57BL/6 mice by administering a high-fat diet (60% fat) for 20 weeks. Throughout this period, KS-25 (50 mg/kg) was administered orally daily. In vivo VAT and systemic inflammation were assessed using ¹⁸F-fluorodeoxyglucose positron emission tomography and C-reactive protein levels. Insulin resistance and glucose intolerance were evaluated through insulin tolerance tests and glucose tolerance tests. Additionally, histological and molecular analyses were conducted on the harvested liver and VAT samples. Results: KS-25 effectively inhibited the TGF-β/Smad3 signaling pathway, leading to a significant reduction in VAT inflammation and associated systemic inflammation induced by a high-fat diet. Additionally, KS-25 markedly enhanced insulin sensitivity, promoted glucose homeostasis, and alleviated hepatic steatosis. These findings suggest that KS-25 plays a crucial role in mitigating VAT inflammation and obesity-related MASLD. Conclusion: Our findings highlight the potential of KS-25 as a promising therapeutic agent for obesity and associated MASLD, specifically through its action on inflamed VAT.